Vrije Universiteit Brussel Cholestatic liver injury induced by food additives, dietary supplements and parenteral nutrition Vilas-Boas, Vânia; Gijbels, Eva; Jonckheer, Joop; De Waele, Elisabeth; Vinken, Mathieu Published in: Environment International DOI: 10.1016/j.envint.2019.105422 10.1016/j.envint.2019.105422 Publication date: 2020 License: CC BY-NC-ND Document Version: Final published version Link to publication Citation for published version (APA): Vilas-Boas, V., Gijbels, E., Jonckheer, J., De Waele, E., & Vinken, M. (2020). Cholestatic liver injury induced by food additives, dietary supplements and parenteral nutrition. 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Oct. 2021 Environment International 136 (2020) 105422 Contents lists available at ScienceDirect Environment International journal homepage: www.elsevier.com/locate/envint Cholestatic liver injury induced by food additives, dietary supplements and T parenteral nutrition ⁎ Vânia Vilas-Boasa, Eva Gijbelsa, Joop Jonckheerb, Elisabeth De Waeleb, Mathieu Vinkena, a Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium b Department of Intensive Care, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium ARTICLE INFO ABSTRACT Handling Editor: Da Chen Cholestasis refers to the accumulation of toxic levels of bile acids in the liver due to defective bile secretion. This Keywords: pathological situation can be triggered by drugs, but also by ingredients contained in food, food supplements and Cholestasis parenteral nutrition. This paper provides an overview of the current knowledge on cholestatic injury associated Food additives with such ingredients, with particular emphasis on the underlying mechanisms of toxicity. Dietary supplements Herbal supplements Parenteral nutrition 1. Introduction pharmaceutical industry (Kullak-Ublick et al., 2017; Lee, 2003). In this particular case, interspecies differences restrict its detection in regular Cholestasis describes any situation of impaired bile flow within the preclinical animal testing. These include differences in BA composition, liver as such (intrahepatic cholestasis) or in the biliary tree (extra- particularly the toxic lithocholic acid, differences in substrate specifi- hepatic cholestasis) leading to the accumulation of toxic levels of bile city of BA transporters, along with differences in metabolic, detox- acids (BAs) (Tanaka et al., 2017). In adult patients it is usually depicted ification and hepatocellular excretion pathways concerning drugs and as an increase in serum levels of alkaline phosphatase (ALP) to more BAs (Yang et al., 2015). Additionally, the knowledge gaps on the me- than twice the upper limit of normal and an alanine aminotransferase chanistic implementation and development of cholestasis have also (ALT) to ALP ratio (ALT/ALP) below 2 (Bjornsson and Jonasson, 2013). been hampering the characterization of this hazard for new drugs and Additionally, although hyperbilirubinemia is not a synonym of cho- chemicals in general. Furthermore, the frequently delayed onset of lestasis, cholestatic injury usually leads to impaired conjugated bilir- cholestasis limits its detection in in vitro models, which in most cases ubin excretion. Therefore, recent guidelines for establishing cholestatic can only be used for short-term studies. A significant effort has been jaundice in infants suggest considering serum levels of direct bilirubin, made in recent years to develop in vitro models that can better mimic mainly conjugated, above 1 mg/dL as a surrogate marker (Fawaz et al., the in vivo human scenario for longer periods of time (Gijbels et al., 2017), but most clinical reports actually refer to values above 2 mg/dL 2019; Vilas-Boas et al., 2019a). Spheroid cultures of primary human (Calkins et al., 2014; Fortenberry et al., 2017; Gao et al., 2018; hepatocytes provide reliable and versatile tools for studying drug-in- Jenniskens et al., 2018). duced cholestasis due to their similarity to the clinical situation and to Cholestasis may be triggered by drugs, which constitutes a subtype the possibility of performing long-term studies (Baze et al., 2018; Bell of drug-induced liver injury (DILI). This is one of the main reasons for et al., 2016; Hendriks et al., 2016). drug withdrawal in pre-marketing and post-marketing phases of drug The main mechanisms so far implicated in the onset of drug-induced development, therefore implying a considerable economic burden for cholestasis are summarized in Fig. 1. These include altered bile Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, anti-mitochondrial antibodies; AOP, adverse outcome pathway; AST, aspartate aminotransferase; BA(s), bile acid(s); BSEP, bile salt export pump; CYP, cytochrome P450; DILI, drug-induced liver injury; EFSA, European Food Safety Authority; ERα, Estrogen receptor alpha; FDA, Food and Drug Administration; FGF19, fibroblast growth factor 19; FGFR4, FGF receptor 4; FXR, Farnesoid X receptor; GPBAR1, G protein-coupled bile acid receptor 1; IL-1β, interleukin 1 beta; LXR, liver X receptor; MRP, multidrug resistance-associated protein; Nrf2, nuclear factor erythroid 2- related factor 2; NTCP, sodium-taurocholate cotransporting polypeptide; PN, parenteral nutrition; PN-AC, PN-associated cholestasis; ROS, reactive oxygen species; RXR, retinoid X receptor; TGR5, Takeda G protein-coupled receptor 5; TNFα, tumor necrosis factor alpha ⁎ Corresponding author. E-mail address: [email protected] (M. Vinken). https://doi.org/10.1016/j.envint.2019.105422 Received 18 September 2019; Received in revised form 5 December 2019; Accepted 13 December 2019 0160-4120/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). V. Vilas-Boas, et al. Environment International 136 (2020) 105422 Fig. 1. Mechanisms of bile acid accumulation and subsequent deteriorative and compensatory responses. The accumulation of BAs triggers an adverse response that may ultimately lead to cell death. An adaptive response is simultaneously activated to counteract the observed unbalance in the BA levels. BA – Bile acid; BSEP – Bile salt export pump; MRP – Multidrug resistance-associated protein; NTCP – Sodium-taurocholate cotransporting polypeptide; FXR – Farnesoid X receptor; CAR – Constitutive androstane receptor; PXR – Pregnane X receptor. canaliculi dynamics, i.e. the constriction/dilation of the bile canaliculi been attributed to contamination with anabolic steroids, known to due to activation/inhibition of the Rho kinase/myosin light chain ki- promote cholestasis (Stolz et al., 2019). Although this represents a nase pathway (Burbank et al., 2016), and hepatocellular changes, such major problem, considering the lack of governmental responsibility in as cytoskeletal alterations and decreased membrane fluidity (Gijbels the assessment of these products’ safety, these cases fall out of the scope et al., 2019). Apart from these, the best described mechanism of drug- of this review paper. On the other hand, given the increased use of induced cholestasis relies on compromised activity of BA transporters. parenteral nutrition, especially in a long-term home setting (Bond et al., The most relevant BA transporters in this context are the bile salt export 2019; Cotogni et al., 2019), the involvement of PN in the onset of pump (BSEP) and the multidrug resistance-associated protein (MRP) 2, cholestasis will be discussed in this manuscript. both exporters of BAs to the bile canaliculi, the MRP3 and MRP4 that export BAs to the sinusoidal blood, and the sodium-taurocholate co- 2. Food additives transporting polypeptide (NTCP) involved in the uptake of BAs from the enterohepatic circulation (Yang et al., 2013). A number of chemicals have been approved as food additives to The subsequent bile accumulation events evoke 2 types of cellular improve the appearance, taste and the stability of food products. This responses, namely an adverse response and an adaptive response. The approval is part of the responsibilities of regulatory bodies, such as the adverse response is accompanied by the onset of processes, such as European Food Safety Authority (EFSA) in Europe and the Food and oxidative stress, inflammation and different cell death modes. The Drug Administration (FDA) in the US. Those chemicals include food adaptive response, aimed at decreasing the uptake and increasing the colorings, preservatives, acidity regulators and antioxidants, emulsifiers export of BAs into and from hepatocytes, respectively, depends on